Preparation method of phenyl ketone amide compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of phenyl ketone amide compounds. The preparation method of the phenyl ketone amide compound comprises the following steps: taking a phenyl acyl silicon compound 1 and an amide compound 2 as raw materials, adding a catalyst, and reacting in a first solvent to prepare the phenyl ketone amide compound 3. The method has the advantages of short and efficient reaction steps, high atom utilization rate, high product yield, mild reaction conditions and wide applicable substrate range, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a phenyl ketone amide compound. Background Art

[0002] α-Ketoamide derivatives have good biological activity. Their bifunctional groups and multi-reaction center characteristics give them special chemical properties. As potential synthetic intermediates, they have broad application prospects in synthetic chemistry, medicinal chemistry and materials science. For example, tacrolimus, a drug for treating eczema, and telaprevir and boceprevir, new drugs for treating hepatitis C, all contain α-ketoamide structural units. In the prior art, α-ketoamides have been successfully synthesized by oxidation reactions, coupling reactions, etc. using alkynamines, keto acids, aryl ketones, aryl iodides and their derivatives as raw materials. However, such reactions usually use heavy metals such as palladium and copper, which have problems such as expensive catalysts and environmental pollution; at the same time, the product yield is greatly affected by the substrate, and the scope of application of the reaction is limited. Therefore, it is of great significance to explore the synthesis method of α-ketoamide compounds with strong universality. Summary of the invention

[0003] The technical problem solved by the present invention is that heavy metals palladium and copper are usually used to synthesize α-ketoamide compounds in the prior art, and the reaction conditions are complex, the cost is high, and the reaction application scope is limited.

[0004] In view of the above technical problems, the object of the present invention is to provide a method for preparing phenylketoamide compounds.

[0005] Specifically, the present invention provides the following technical solutions:

[0006] In a first aspect, the present invention provides a method for preparing a phenylketoamide compound, comprising the following steps:

[0007] A phenyl acyl silicon compound 1 and an amide compound 2 are used as raw materials, a catalyst is added, and the reaction is carried out in a first solvent to prepare a phenyl ketone amide compound 3. The reaction route is any one of the following two reaction routes:

[0008] The first reaction route:

[0009]

[0010] The second reaction route:

[0011]

[0012] Among them, the R1 group The ortho, meta and / or para position of the group; n is 1 to 3;

[0013] The R1 group is selected from hydrogen, C1-6 Alkyl, C 1-6 Alkoxy, halogen or substituted C 1-6 wherein the substituent is selected from one or more of methyl, tert-butyl, methoxy, butoxy, -F and -Cl;

[0014] The R2 group and the R3 group are independently selected from H or C 1-6 alkyl;

[0015] The R4 group is a silicon-containing group;

[0016] The R5 group is selected from Wherein, the R6 group is connected to any carbon atom on the nitrogen-containing ring, and the R6 group is selected from H, C 1-7 Alkyl or C 1-7 of alkoxy.

[0017] Preferably, the silicon-containing group is a group in which the three substituents on the silicon atom are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, benzyl, C 1-3 Alkyl-substituted phenyl, styryl, hydroxy-substituted styryl or trimethylsilyl.

[0018] Preferably, the silicon-containing group is trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, methylbutylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-dimethylphenylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, 2-hydroxystyryldiisopropylsilyl, tert-butyloxymethylphenylsilyl or tert-butoxydiphenylsilyl.

[0019] Preferably, the silicon-based protecting group is trimethylsilyl or triethylsilyl.

[0020] Preferably, in the first or second reaction route, the R1 group is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, methoxy, butoxy or -Cl.

[0021] Preferably, in the first reaction route, the R2 and R3 groups are independently selected from methyl, ethyl, propyl or n-butyl.

[0022] Preferably, in the second reaction route, the R5 group is selected from

[0023] Preferably, the molar ratio of the phenyl acyl silicon compound 1 to the amide compound 2 is 1-4:1-3.

[0024] Preferably, the molar ratio of the phenyl acyl silicon compound 1 to the amide compound 2 is 2.5-3.5:1.5-2.5.

[0025] More preferably, the molar ratio of the phenyl acyl silicon compound 1 to the amide compound 2 is 2.7-3.3:1.7-2.3.

[0026] Preferably, the reaction temperature is -110°C to -40°C; preferably, the reaction temperature is -100°C to -70°C.

[0027] Preferably, the reaction time is 0.5 to 5 hours.

[0028] Preferably, the catalyst is selected from one or more of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.

[0029] Preferably, the catalyst is selected from lithium diisopropylamide.

[0030] More preferably, the molar ratio of the catalyst to the compound 1 is 1-8:1-4.

[0031] More preferably, the molar ratio of the catalyst to the compound 1 is 6-8:2-4.

[0032] Most preferably, the molar ratio of the catalyst to the compound 1 is 6.5-7.5:2.5-3.5.

[0033] Preferably, the first solvent includes one or more of tetrahydrofuran, methyl tert-butyl ether, toluene, diethyl ether and dichloromethane.

[0034] Preferably, the first solvent is tetrahydrofuran.

[0035] More preferably, the volume ratio of the amount of the compound 1 to the first solvent is 1:0.5-6, wherein the unit of the amount of the compound 1 is mol and the unit of the volume is L.

[0036] More preferably, the volume ratio of the amount of the compound 1 to the first solvent is 1:1-5, wherein the unit of the amount of the compound 1 is mol and the unit of the volume is L.

[0037] More preferably, the volume ratio of the amount of the compound 1 to the first solvent is 1:1-3, wherein the unit of the amount of the compound 1 is mol and the unit of the volume is L.

[0038] Preferably, after the reaction is completed, a second solvent is added to quench the reaction to obtain phenylketoamide compound 3.

[0039] Preferably, the second solvent is water or a saturated aqueous ammonium chloride solution.

[0040] More preferably, the ratio of the volume of the second solvent to the amount of compound 1 is 1 to 15:1, preferably 5 to 8:1, wherein the unit of the amount of the substance is mol and the unit of volume is L.

[0041] Preferably, the second solvent is added to quench the reaction, and then concentrated under reduced pressure; more preferably, concentrated under reduced pressure at 20-50° C.; and / or for 10-60 min.

[0042] Preferably, the product after reduced pressure concentration is purified, and the purification is column chromatography separation and purification.

[0043] More preferably, the eluent is petroleum ether and ethyl acetate.

[0044] More preferably, the volume ratio of petroleum ether to ethyl acetate is 2 to 15:1.

[0045] Preferably, the gas atmosphere during the preparation process is N2 gas atmosphere or Ar gas atmosphere.

[0046] Preferably, the phenyl ketone amide compound 3 is any one of the following compounds:

[0047] Compound 3a: n = 1, R1 is in the para position, R1 is -CH3, R2 is -CH3, and R3 is -CH3;

[0048] Compound 3b: n=1, R1 is in the para position, R1 is -CH3, R2 is -CH2CH3, and R3 is -CH2CH3;

[0049] Compound 3c: n = 1, R1 is in the para position, R1 is -CH3, R5 is

[0050] Compound 3d: n = 1, R1 is in the para position, R1 is -CH3, R2 is -CH2CH2CH3, R 3 is -CH2CH2CH3;

[0051] Compound 3e: n=1, R1 is in the para position, R1 is -CH3, R2 is -CH2CH2CH2CH3, and R3 is -CH2CH2CH2CH3;

[0052] Compound 3f: n = 1, R1 is in the para position, R1 is -CH3, R5 is

[0053] Compound 3g: n = 1, R1 is in the para position, R1 is -H, R2 is -CH3, and R3 is -CH3;

[0054] Compound 3h: n = 1, R1 is in the para position, R1 is -C(CH3)3, R2 is -CH3, and R3 is -CH3;

[0055] Compound 3i: n = 1, R1 is in the para position, R1 is -Cl, R2 is -CH3, and R3 is -CH3;

[0056] Compound 3j: n = 1, R1 is in the para position, R1 is -OCH3, R2 is -CH3, and R3 is -CH3;

[0057] Compound 3k: n = 1, R1 is in the para position, R1 is -OCH2CH2CH2CH3, R2 is -CH3, and R3 is -CH3;

[0058] Compound 3l: n = 1, R1 is in the ortho position, R1 is -CH3, R2 is -CH3, and R3 is -CH3;

[0059] Compound 3m: n = 1, R1 is at the meta position, R1 is -CH3, R2 is -CH3, and R3 is -CH3;

[0060] Compound 3n: n=2, R1 is in the meta position, R1 is -CH3, R2 is -CH3, and R3 is -CH3.

[0061] Beneficial effects of the present invention:

[0062] (1) In the present invention, amide compounds are used as nucleophilic reagents to synthesize phenyl α-ketoamide compounds with potential application value in one step. The reaction steps are short and efficient, the atomic utilization rate is high, and the yield of the obtained product is high.

[0063] (2) The preparation method of the present invention has low cost. The raw materials ketone, amide compound and catalyst used in the present invention are simple and easy to obtain.

[0064] (3) The preparation method of the present invention has mild reaction conditions, is applicable to a wide range of substrates, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 is the phenyl ketone amide compound (3a) in Example 1 1 H NMR spectra.

[0066] Figure 2 is the phenyl ketone amide compound (3a) in Example 1 13 C NMR spectrum.

[0067] Figure 3 is the phenyl ketone amide compound (3b) in Example 2 1 H NMR spectra.

[0068] Figure 4is the phenyl ketone amide compound (3b) in Example 2 13 C NMR spectrum.

[0069] Figure 5 is the phenyl ketone amide compound (3c) in Example 3 1 H NMR spectra.

[0070] Figure 6 is the phenyl ketone amide compound (3c) in Example 3 13 C NMR spectrum.

[0071] Figure 7 is the phenyl ketone amide compound (3d) in Example 4 1 H NMR spectra.

[0072] Figure 8 is the phenyl ketone amide compound (3d) in Example 4 13 C NMR spectrum.

[0073] Fig. 9 is the phenyl ketone amide compound (3e) in Example 5 1 H NMR spectra.

[0074] Fig.10 is the phenyl ketone amide compound (3e) in Example 5 13 C NMR spectrum.

[0075] Fig.11 is the phenyl ketone amide compound (3f) in Example 6 1 H NMR spectra.

[0076] Fig.12 is the phenyl ketone amide compound (3f) in Example 6 13 C NMR spectrum.

[0077] Fig.13 is the phenyl ketone amide compound (3g) in Example 7 1 H NMR spectra.

[0078] Fig.14 is the phenyl ketone amide compound (3g) in Example 7 13 C NMR spectrum.

[0079] Fig.15 is the phenyl ketone amide compound (3h) in Example 8 1 H NMR spectra.

[0080] Fig.16 is the phenyl ketone amide compound (3h) in Example 8 13 C NMR spectrum.

[0081] Fig.17 is the phenyl ketone amide compound (3i) in Example 9 1 H NMR spectra.

[0082] Fig.18 is the phenyl ketone amide compound (3i) in Example 9 13 C NMR spectrum.

[0083] Fig.19 is the phenyl ketone amide compound (3j) in Example 10 1 H NMR spectra.

[0084] Fig. 20 is the phenyl ketone amide compound (3j) in Example 10 13 C NMR spectrum.

[0085] Fig.21 is the phenyl ketone amide compound (3k) in Example 11 1 H NMR spectra.

[0086] Fig. 22 is the phenyl ketone amide compound (3k) in Example 11 13 C NMR spectrum.

[0087] Fig.23 is the phenyl ketone amide compound (31) in Example 12 1 H NMR spectra.

[0088] Fig.24 is the phenyl ketone amide compound (31) in Example 12 13 C NMR spectrum.

[0089] Fig.25 is the phenyl ketone amide compound (3m) in Example 13 1 H NMR spectra.

[0090] Fig.26 is the phenyl ketone amide compound (3m) in Example 13 13 C NMR spectrum.

[0091] Fig. 27 is the phenyl ketone amide compound (3n) in Example 14 1 H NMR spectra.

[0092] Fig.28 is the phenyl ketone amide compound (3n) in Example 14 13 C NMR spectrum. DETAILED DESCRIPTION

[0093] As mentioned above, the object of the present invention is to provide a method for preparing phenyl ketone amide compounds.

[0094] In the present invention, acyl silicon compound is used as raw material, and formamide and its derivatives, which are simple and readily available conventional solvents, are used as nucleophilic reagents to directly synthesize phenyl ketoamide compounds under alkaline conditions. The method has readily available raw materials, a wide range of substrates, convenient reaction operation, high atom economy, and is suitable for industrial production.

[0095] In the present invention, “C i～j " indicates that the number of carbon atoms is an integer from i to j. For example, C 1～6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms (including 1 and 6). 2-6 The alkenyl group refers to an alkenyl group containing 2 to 6 carbon atoms (inclusive).

[0096] The term "substituted" means that any available connection point in the structure can be substituted by a substituent, including but not limited to carboxyl, amino, nitroso, alcohol hydroxyl, halogen group or hydrocarbon group.

[0097] The present invention provides a method for preparing a phenylketoamide compound, which comprises the following steps:

[0098] A phenyl acyl silicon compound 1 and an amide compound 2 are used as raw materials, a catalyst is added, and the reaction is carried out in a first solvent to prepare a phenyl ketone amide compound 3. The reaction route is any one of the following two reaction routes:

[0099] The first reaction route:

[0100]

[0101] The second reaction route:

[0102]

[0103] Among them, the R1 group The ortho, meta and / or para position of the group; n is 1 to 3;

[0104] The R1 group is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen or substituted C 1-6 wherein the substituent is selected from one or more of methyl, tert-butyl, methoxy, butoxy, F and Cl;

[0105] The R2 group and the R3 group are independently selected from H or C 1-6 alkyl;

[0106] The R4 group is a silicon-containing group;

[0107] The R5 group is selected from Wherein, the R6 group is connected to any carbon atom on the nitrogen-containing ring, and the R6 group is selected from H, C 1-7 An alkyl or alkoxy group.

[0108] in, The R6 group can be attached to any carbon atom on the ring. For example, express express and / or

[0109] Preferably, the first solvent is tetrahydrofuran, which is easy to recycle and has low environmental pollution.

[0110] Preferably, formamide compounds are used as nucleophilic reagents, the raw materials are cheap and readily available, and the reaction operation is convenient.

[0111] Preferably, the phenyl ketone amide compound 3 is any one of the following compounds:

[0112]

[0113] Unless otherwise specified, the various reagents / instruments used in the examples and comparative examples of the present invention are conventional commercially available products. The experimental materials and instrument information used in the present invention are shown in the following table:

[0114] Table 1 Experimental materials and manufacturers

[0115]

[0116]

[0117] Among them, the acylsilane compound in the present invention is obtained by referring to the preparation method recorded in the journal ("Nucleophilic Allylation of Acylsilanes in Water: An Effective Alternative to Functionalized Tertiary α-Silylalcohols", Xiu-Xia Liang, et al., "The Journal of Organic Chemistry", 2023, 88, 16, 12087-12099), and the compound successfully prepared has been proved by 1H NMR and 13CNMR characterization.

[0118] In order to better understand the technical solution of the present invention, the technical solution of the present invention is described in detail below in conjunction with specific embodiments.

[0119] Example 1: Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0120] Example 1-1

[0121] (1) Preparation of p-Tolyl(triethylsilyl)ketone

[0122]

[0123] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of p-tolualdehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-p-tolyl-1,3-dithiane.

[0124] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to 2-p-tolyl-1,3-dithiane (10.2mmol) in tetrahydrofuran (THF) (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=100:1) to obtain triethyl(2-(p-tolyl)-1,3-dithiophen-2-yl)silane.

[0125] 3) In an air atmosphere at 0°C, acetone and water (volume ratio of acetone: water is 6:7) were added to triethyl (2- (p-tolyl) -1,3-dithiophene-2-yl) silane (0.93g, 2.857mmol), NBS (11.24mmol) was added thereto, and the reaction was continued for 30min. The mixture was diluted with water (10mL) and extracted with EtOAc (10mL), anhydrous sodium sulfate was added to remove water, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) to dryness. The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1), to obtain p-tolyl (triethylsilyl) ketone.

[0126] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0127]

[0128] Under a nitrogen atmosphere at -78°C, N,N-dimethylformamide (DMF) (0.2 mmol) was added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol), and after the solution was cooled to -78°C, lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) was added. After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (27.51 mg, yield 72% (based on the molar amount of DMF), compound 3a).

[0129] The structural characterization data of compound 3a are as follows:

[0130] from Figure 1 You can get: 1 HNMR (600MHz, CDCl3) δ7.84 (d, J = 8.4Hz, 2H), 7.30 (d, J = 7.8Hz, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.43 (s, 3H).

[0131] from Figure 2 You can get: 13 C NMR (150MHz, CDCl3) δ191.6,167.3,146.1,130.7,129.83,129.80,37.1,34.0,22.0.

[0132] HRMS(ESI): Molecular formula C 11 H 13 NO2, m / z[M+Na] + The theoretical value is 214.0838 and the actual value is 214.0835.

[0133] Example 1-2

[0134] (1) Step (1) is the same as in Example 1-1.

[0135] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0136] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.1 mL, 0.2 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.2 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, yield 9%).

[0137] Examples 1-3

[0138] (1) Step (1) is the same as in Example 1-1.

[0139] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0140] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.1 mL, 0.2 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.4 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, yield 31%).

[0141] Examples 1-4

[0142] (1) Step (1) is the same as in Example 1-1.

[0143] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0144] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.1 mL, 0.2 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.6 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, yield 32%).

[0145] Examples 1-5

[0146] (1) Step (1) is the same as in Example 1-1.

[0147] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0148] Under a nitrogen atmosphere at -78°C, DMF (0.4 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.1 mL, 0.2 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.2 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, yield 6%).

[0149] Examples 1-6

[0150] (1) Step (1) is the same as in Example 1-1.

[0151] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0152] Under a nitrogen atmosphere at -100°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The product was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, yield 67%).

[0153] Examples 1-7

[0154] (1) Step (1) is the same as in Example 1-1.

[0155] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0156] Under a nitrogen atmosphere at -50°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, yield 4%).

[0157] Examples 1-8

[0158] (1) Step (1) is the same as in Example 1-1.

[0159] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0160] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 2 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 70%).

[0161] Examples 1-9

[0162] (1) Step (1) is the same as in Example 1-1.

[0163] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0164] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium bis(trimethylsilyl)amide (0.7 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1 hour, water (2 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 3%).

[0165] Examples 1-10

[0166] (1) Step (1) is the same as in Example 1-1.

[0167] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0168] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and sodium bis(trimethylsilyl)amide (0.7 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1 hour, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 2%).

[0169] Examples 1-11

[0170] (1) Step (1) is the same as in Example 1-1.

[0171] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0172] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and potassium bis(trimethylsilyl)amide (0.7 mmol) were added to a THF solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1 hour, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 2%).

[0173] Examples 1-12

[0174] (1) Step (1) is the same as in Example 1-1.

[0175] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0176] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a solution of p-tolyl(triethylsilyl)ketone (0.3 mmol) in methyl tert-butyl ether (0.6 mL). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 50%).

[0177] Examples 1-13

[0178] (1) Step (1) is the same as in Example 1-1.

[0179] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0180] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a toluene solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 49%).

[0181] Examples 1-14

[0182] (1) Step (1) is the same as in Example 1-1.

[0183] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0184] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a solution of p-tolyl(triethylsilyl)methanone (0.3 mmol) in ether (0.6 mL). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 49%).

[0185] Examples 1-15

[0186] (1) Step (1) is the same as in Example 1-1.

[0187] (2) Preparation of N,N-dimethyl-2-oxo-2-p-tolylacetamide

[0188] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and lithium diisopropylamide LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a dichloromethane solution (0.6 mL) of p-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-p-tolylacetamide (compound 3a, 1%).

[0189] Example 2: Preparation of N,N-diethyl-2-oxo-2-p-tolylacetamide

[0190]

[0191] (1) The preparation steps of p-tolyl(triethylsilyl)ketone are the same as those in Example 1.

[0192] (2) Preparation of N,N-diethyl-2-oxo-2-p-tolylacetamide

[0193] Under a nitrogen atmosphere at -78°C, N,N-diethylformamide (0.2mmol) and LDA (2mol / L, 0.35mL, 0.7mmol) were added to a THF solution (0.6mL) of p-tolyl(triethylsilyl)ketone (0.3mmol). After stirring for 4.5 hours, water (2mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give N,N-diethyl-2-oxo-2-p-tolylacetamide (35.48mg, 81%, compound 3b).

[0194] The structural characterization data of compound 3b are as follows:

[0195] from Figure 3 You can get: 1 HNMR(600MHz, CDCl3)δ7.80(d,J=8.4Hz,2H),7.27(d,J=8.4Hz,2H),3.53(q,J=7.2Hz, 2H), 3.21 (q, J = 7.2Hz, 2H), 2.40 (s, 3H), 1.26 (t, J = 7.2Hz, 3H), 1.12 (t, J = 7.2Hz, 3H).

[0196] from Figure 4 You can get: 13C NMR (150MHz, CDCl3) δ191.5,167.0,145.8,130.9,129.79,129.75,42.2,38.8,21.9,14.2,12.9.

[0197] HRMS(ESI):Molecular formula C 13 H 17 NO2, m / z [M+H] + The theoretical value is 220.1332, and the actual value is 220.1332.

[0198] Example 3: Preparation of 1-(piperidin-1-yl)-2-p-tolylethane-1,2-dione

[0199]

[0200] (1) The preparation steps of p-tolyl(triethylsilyl)ketone are the same as those in Example 1.

[0201] (2) Preparation of 1-(piperidin-1-yl)-2-(p-tolyl)ethane-1,2-dione

[0202] Under a nitrogen atmosphere at -78°C, piperidine-1-carboxaldehyde (0.2mmol) and LDA (2mol / L, 0.35mL, 0.7mmol) were added to a THF solution (1.0mL) of p-tolyl(triethylsilyl)methanone (0.3mmol). After stirring for 1.5 hours, water (2mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain 1-piperidin-1-yl-2-p-tolylethane-1,2-dione (37.42mg, 81%, compound 3c).

[0203] The structural characterization data of compound 3c are as follows:

[0204] from Figure 5 You can get: 1 H NMR (600MHz, CDCl3) δ7.84(d,J=8.4Hz,2H),7.31(d,J=7.8Hz,2H),3.70(s,2H),3.28(t,J=6.6Hz,2H),2.43(s,3H),1.69(s,4H),1.54(s,2H).

[0205] from Figure 6 You can get: 13C NMR (150MHz, CDCl3) δ191.8,165.8,146.0,131.0,129.83,129.81,47.2,42.2,26.3,25.6,24.5,22.0.

[0206] HRMS(ESI): Molecular formula C 14 H 17 NO2, m / z [M+H] + The theoretical value is 232.1332, and the actual value is 232.1331.

[0207] Example 4: Preparation of 2-oxo-N,N-dipropyl-2-(p-tolyl)acetamide

[0208]

[0209] (1) The preparation steps of p-tolyl(triethylsilyl)ketone are the same as those in Example 1.

[0210] (2) Preparation of 2-oxo-N,N-dipropyl-2-(p-tolyl)acetamide

[0211] Under a nitrogen atmosphere at -78°C, N,N-dipropylformamide (0.2mmol) and LDA (2mol / L, 0.35mL, 0.7mmol) were added to a THF solution (0.6mL) of p-tolyl(triethylsilyl)ketone (0.3mmol). After stirring for 1 hour, water (2mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give 2-oxo-N,N-dipropyl-2-(p-tolyl)acetamide (41.99mg, 85%, compound 3d).

[0212] The structural characterization data of compound 3d are as follows:

[0213] from Figure 7 You can get: 1 H NMR (600MHz, CDCl3) δ7.83(d,J=8.4Hz,2H),7.29(d,J=7.8Hz,2H),3.46(t,J=7.8Hz,2H),3.11(t,J=7.8 Hz,2H),2.43(s,3H),1.74–1.6(m,2H),1.60–1.54(m,2H),1.00(t,J=7.8Hz,3H),0.78(t,J=7.8Hz,3H).

[0214] from Figure 8 You can get: 13C NMR (150MHz, CDCl3) δ191.5,167.5,145.8,131.1,129.9,129.8,49.5,45.9,22.0,21.9,20.8,11.6,11.2.

[0215] HRMS(ESI): Molecular formula C 15 H 21 NO2, m / z [M+H] + The theoretical value is 248.1645 and the actual value is 248.1648.

[0216] Example 5: Preparation of N,N-dibutyl-2-oxo-2-p-tolylacetamide

[0217]

[0218] (1) The preparation steps of p-tolyl(triethylsilyl)ketone are the same as those in Example 1.

[0219] (2) Preparation of N,N-dibutyl-2-oxo-2-p-tolylacetamide

[0220] Under a nitrogen atmosphere at -78°C, N,N-dibutylformamide (0.2mmol) and LDA (2mol / L, 0.35mL, 0.7mmol) were added to a THF solution (0.6mL) of p-tolyl(triethylsilyl)ketone (0.3mmol). After stirring for 2 hours, water (2mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give N,N-dibutyl-2-oxo-2-p-tolylacetamide (47.85mg, 87%, compound 3e).

[0221] The structural characterization data of compound 3e are as follows:

[0222] from Fig. 9 It can be obtained: H NMR (600 MHz, CDCl3) δ7.81 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 3.48 (t, J = 7.8 Hz, 2H), 3.13 (t, J = 7.8 Hz, 2H), 2.42 (s, 3H), 1.68–1.63 (m, 2H), 1.54–1.49 (m, 2H), 1.43–1.37 (m, 2H), 1.20–1.14 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H).

[0223] from Fig.10 You can get:13 C NMR (150MHz, CDCl3) δ191.5,167.4,145.8,131.1,129.82,129.75,47.5,44.1,30.7,29.6,22.0,20.4,19.9,14.0,13.7.

[0224] HRMS(ESI): Molecular formula C 17 H 25 NO2, m / z [M+H] + The theoretical value is 276.1958 and the actual value is 276.1960.

[0225] Example 6: Preparation of 1-azepine-1-yl-2-p-tolylethane-1,2-dione

[0226]

[0227] (1) The preparation steps of p-tolyl(triethylsilyl)ketone are the same as those in Example 1.

[0228] (2) Preparation of 1-azepine-1-yl-2-p-tolylethane-1,2-dione

[0229] Under a nitrogen atmosphere at -78°C, hexahydro-1H-azepine-1-carbaldehyde (0.2mmol) and LDA (2mol / L, 0.35mL, 0.7mmol) were added to a THF solution (0.6mL) of p-tolyl(triethylsilyl)methanone (0.3mmol). After stirring for 1.5 hours, water (2mL) was added to quench the reaction. The mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give 1-azepine-1-yl-2-p-tolylethane-1,2-dione (39.69mg, 81%, compound 3f).

[0230] The structural characterization data of compound 3f are as follows:

[0231] from Fig.11 You can get: 1 H NMR (600MHz, CDCl3) δ7.84(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),3.67(t,J=6.0Hz,2H),3 .33(t,J=6.0Hz,2H),2.43(s,3H),1.86–1.82(m,2H),1.69–1.64(m,4H),1.60–1.57(d,2H).

[0232] from Fig.12 You can get:13 C NMR (150MHz, CDCl3) δ191.7,167.5,145.9,131.0,129.9,129.8,48.1,45.2,29.2,27.8,27.4,26.7,22.0.

[0233] HRMS(ESI): Molecular formula C 15 H 19 NO2, m / z [M+H] + The theoretical value is 246.1489, and the actual value is 246.1489.

[0234] Example 7: Preparation of N,N-dimethyl-2-oxo-2-phenylacetamide

[0235] (1) Preparation of phenyl(triethylsilyl)ketone

[0236]

[0237] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of benzaldehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-phenyl-1,3-dithiane.

[0238] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (1.71mL, 10.2mmol) were added to a solution of 2-phenyl-1,3-dithiane (2.0g, 10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain triethyl(2-phenyl-1,3-dithiophen-2-yl)silane.

[0239] 3) In an air atmosphere at 0°C, acetone and water (volume ratio of acetone: water is 6:7) were added to triethyl(2-phenyl-1,3-dithiophene-2-yl)silane (2.87mmol), and NBS (11.24mmol) was added thereto, and the reaction was continued for 30min. The mixture was diluted with water (10mL) and extracted with EtOAc (10mL), and anhydrous sodium sulfate was added to remove water and then concentrated under reduced pressure (evaporation at 35°C for 40min). Phenyl(triethylsilyl)ketone was obtained by separation and purification by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1).

[0240] (2) Preparation of N,N-dimethyl-2-oxo-2-phenylacetamide

[0241]

[0242] Under a nitrogen atmosphere at -78°C, DMF (0.2mmol) and LDA (2mol / L, 0.35mL, 0.7mmol) were added to a THF solution (0.6mL) of phenyl(triethylsilyl)ketone (0.3mmol). After stirring for 2 hours, water (2mL) was added to quench the reaction. The mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give N,N-dimethyl-2-oxo-2-phenylacetamide (27.26mg, 77%, compound 3g).

[0243] The structural characterization data of compound 3g are as follows:

[0244] from Fig.13 You can get: 1 H NMR (600MHz, CDCl3) δ7.89 (d, J=7.2Hz, 2H), 7.59 (t, J=7.2Hz, 1H), 7.46 (t, J=7.2Hz, 2H), 3.06 (s, 3H), 2.90 (s, 3H).

[0245] from Fig.14 You can get: 13 C NMR (150MHz, CDCl3) δ191.8,167.0,134.7,133.0,129.6,129.0,37.0,33.9.

[0246] HRMS(ESI): Molecular formula C 10 H 11 NO2, m / z[M+Na] + The theoretical value is 200.0682 and the actual value is 200.0687.

[0247] Example 8: Preparation of 2-(4-tert-butyl)phenyl-N,N-dimethyl-2-oxoacetamide

[0248] (1) Preparation of ((4-tert-butyl)phenyl)(triethylsilyl)methanone

[0249]

[0250] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of 4-(tert-butyl)benzaldehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-(4-tert-butyl)phenyl-1,3-dithiane.

[0251] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to 2-(4-tert-butyl)phenyl-1,3-dithiane (10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction. After concentration under reduced pressure (evaporation at 35°C for 40min), the mixture was separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-(4-tert-butyl)phenyl-1,3-dithien-2-yl)triethylsilane.

[0252] 3) Under 0°C air atmosphere, acetone and water (volume ratio of acetone: water is 6:7) were added to 2-(4-tert-butyl)phenyl-1,3-dithiophen-2-yl)triethylsilane (2.857mmol), and NBS (11.24mmol) was added thereto, and the reaction was continued for 30min. The mixture was diluted with water (10mL) and extracted with EtOAc (10mL), and anhydrous sodium sulfate was added to remove water and concentrated under reduced pressure (evaporation at 35°C for 40min). The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1), to obtain (4-tert-butyl)phenyl(triethylsilyl)ketone.

[0253] (2) Preparation of 2-(4-tert-butyl)phenyl-N,N-dimethyl-2-oxoacetamide

[0254]

[0255] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of (4-tert-butyl)phenyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give 2-(4-tert-butyl)phenyl-N,N-dimethyl-2-oxoacetamide (36.81 mg, 79%, compound 3h).

[0256] The structural characterization data of compound 3h are as follows:

[0257] from Fig.15 You can get: 1 H NMR (600MHz, CDCl3) δ7.87 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 1.34 (s, 9H).

[0258] from Fig.16 You can get: 13 C NMR (150MHz, CDCl3) δ191.7,167.4,158.9,130.7,129.8,126.2,37.2,35.5,34.1,31.1.

[0259] HRMS(ESI): Molecular formula C 14 H 19 NO2, m / z [M+H] + The theoretical value is 234.1489 and the actual value is 234.1485.

[0260] Example 9: Preparation of 2-(4-chlorophenyl)-N,N-dimethyl-2-oxoacetamide

[0261] (1) Preparation of (4-chlorophenyl) (triethylsilyl) ketone

[0262]

[0263] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of p-chlorobenzaldehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-(4-chlorophenyl)-1,3-dithiane.

[0264] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to 2-(4-chlorophenyl)-1,3-dithiane (2.35g, 10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain (2-(4-chlorophenyl)-1,3-dithiane-2-yl)triethylsilane.

[0265] 3) Under 0°C air atmosphere, acetone and water (volume ratio of acetone: water is 6:7) were added to (2-(4-chlorophenyl)-1,3-dithian-2-yl)triethylsilane (0.98 g, 2.857 mmol), and NBS (2.0 g, 11.24 mmol) was added thereto, and the reaction was continued for 30 min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL), and anhydrous sodium sulfate was added to remove the water and then concentrated under reduced pressure (evaporated at 35°C for 40 min). The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1), to obtain (4-chlorophenyl) (triethylsilyl) ketone.

[0266] (2) Preparation of 2-(4-chlorophenyl)-N,N-dimethyl-2-oxoacetamide

[0267]

[0268] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of (4-chlorophenyl)(triethylsilyl)methanone (0.3 mmol). After stirring for 2 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give 2-(4-chlorophenyl)-N,N-dimethyl-2-oxoacetamide (36.29 mg, 86%, compound 3i).

[0269] The structural characterization data of compound 3i are as follows:

[0270] from Fig.17 You can get: 1H NMR (600MHz, CDCl3) δ7.89 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 3.11 (s, 3H), 2.96 (s, 3H).

[0271] from Fig.18 You can get: 13 C NMR (150MHz, CDCl3) δ190.4,166.6,141.5,131.6,131.2,129.5,37.2,34.2.

[0272] HRMS(ESI): Molecular formula C 10 H 10 ClNO2, m / z[M+H] + The theoretical value is 212.0473 and the actual value is 212.0470.

[0273] Example 10: Preparation of 2-(4-methoxyphenyl)-N,N-dimethyl-2-oxoacetamide

[0274] (1) Preparation of (4-methoxyphenyl) (triethylsilyl) ketone

[0275]

[0276] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of 4-methoxybenzaldehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-(4-methoxyphenyl)-1,3-dithiane.

[0277] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to 2-(4-methoxyphenyl)-1,3-dithiane (10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=100:1) to obtain triethyl(2-(4-methoxyphenyl)-1,3-dithiophen-2-ylsilane).

[0278] 3) Under 0°C air atmosphere, acetone and water (volume ratio of acetone: water is 6:7) were added to triethyl (2-(4-methoxyphenyl)-1,3-dithiophene-2-ylsilane) (0.97 g, 2.857 mmol), NBS (2.0 g, 11.24 mmol) was added thereto, and the reaction was carried out for 30 min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL), anhydrous sodium sulfate was added to remove water, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40 min). The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1) to obtain (4-methoxyphenyl) (triethylsilyl) ketone.

[0279] (2) Preparation of 2-(4-methoxyphenyl)-N,N-dimethyl-2-oxoacetamide

[0280]

[0281] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of (4-methoxyphenyl)(triethylsilyl)methanone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give 2-(4-methoxyphenyl)-N,N-dimethyl-2-oxoacetamide (37.26 mg, 90%, compound 3j).

[0282] The structural characterization data of compound 3j are as follows:

[0283] from Fig.19 You can get: 1 H NMR (600MHz, CDCl3) δ7.90 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H), 3.09 (s, 3H), 2.94 (s, 3H).

[0284] from Fig. 20 You can get: 13 C NMR (150MHz, CDCl3) δ190.6,167.5,165.0,132.2,126.3,114.4,55.8,37.2,34.1.

[0285] HRMS(ESI): Molecular formula C 11 H 13 NO3, m / z[M+H] +The theoretical value is 208.0968 and the actual value is 208.0966.

[0286] Example 11: Preparation of 2-(4-butoxyphenyl)-N,N-dimethyl-2-oxoacetamide

[0287] (1) Preparation of (4-butoxyphenyl) (triethylsilyl) ketone

[0288]

[0289] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of 4-butoxybenzaldehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-(4-butoxyphenyl)-1,3-dithiane.

[0290] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to 2-(4-butoxyphenyl)-1,3-dithiane (10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction. After concentration under reduced pressure (evaporation at 35°C for 40min), the mixture was separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain triethyl(2-(4-butoxyphenyl))-1,3-dithiophene-2-ylsilane.

[0291] 3) At 0°C in air atmosphere, add acetone and water (volume ratio of acetone: water is 6:7) to triethyl (2- (4-butoxyphenyl)) -1,3-dithiophene-2-ylsilane (2.857mmol), add NBS (2.0g, 11.24mmol), and react for 30min. Dilute with water (10mL) and extract with EtOAc (10mL), add anhydrous sodium sulfate to remove water and evaporate to dryness. Separate and purify by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as eluent to obtain (4-butoxyphenyl) (triethylsilyl) ketone.

[0292] (2) Preparation of 2-(4-butoxyphenyl)-N,N-dimethyl-2-oxoacetamide

[0293]

[0294] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of (4-butoxyphenyl)(triethylsilyl)methanone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain 2-(4-butoxyphenyl)-N,N-dimethyl-2-oxoacetamide (43.33 mg, 87%, compound 3k).

[0295] The structural characterization data of compound 3j are as follows:

[0296] from Fig.21 You can get: 1 H NMR (600MHz, CDCl3) δ7.89 (d, J = 9.0Hz, 2H), 6.95 (d, J = 8.4Hz, 2H), 4.04 (t, J = 6.6Hz, 2H) ,3.10(s,3H),2.95(s,3H),1.81–1.76(m,2H),1.52–1.46(m,2H),0.98(t,J=7.2Hz,3H).

[0297] from Fig. 22 You can get: 13 C NMR (150MHz, CDCl3) δ190.6,167.6,164.6,132.2,126.1,114.9,68.3,37.2,34.1,31.2,19.3,13.9.

[0298] HRMS(ESI): Molecular formula C 14 H 19 NO3, m / z[M+Na] + The theoretical value is 272.1257 and the actual value is 272.1255.

[0299] Example 12: Preparation of N,N-dimethyl-2-oxo-2-(o-tolyl)acetamide

[0300] (1) Preparation of o-tolyl(triethylsilyl)ketone

[0301]

[0302] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of o-tolualdehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain o-tolyl-1,3-dithiane.

[0303] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to o-tolyl-1,3-dithiane (10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain triethyl(2-(o-tolyl)-1,3-dithiane-2-yl)silane.

[0304] 3) Under 0°C air atmosphere, acetone and water (volume ratio of acetone: water is 6:7) were added to triethyl (2-(o-tolyl)-1,3-dithian-2-yl) silane (2.857mmol), NBS (11.24mmol) was added thereto, and the reaction was continued for 30min. The mixture was diluted with water (10mL) and extracted with EtOAc (10mL), and anhydrous sodium sulfate was added to remove water and then concentrated under reduced pressure (evaporation at 35°C for 40min). The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1), to obtain o-tolyl (triethylsilyl) ketone.

[0305] (2) Preparation of N,N-dimethyl-2-oxo-2-(o-tolyl)acetamide

[0306]

[0307] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of o-tolyl(triethylsilyl)methanone (0.3 mmol). After stirring for 2 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-(o-tolyl)acetamide (17.95 mg, 47%, compound 31).

[0308] The structural characterization data of compound 3l are as follows:

[0309] from Fig.23 You can get: 1 H NMR (600MHz, CDCl3) δ7.67 (d, J = 7.8Hz, 1H), 7.44-7.47 (m, 1H), 7.28-7.29 (m, 2H), 3.09 (s, 3H), 2.95 (s, 3H), 2.64 (s, 3H).

[0310] from Fig.24 You can get: 13 C NMR (150MHz, CDCl3) δ193.9,167.9,141.5,133.8,132.72,132.66,131.6,126.3,37.1,34.1,21.8.

[0311] HRMS(ESI): Molecular formula C 11 H 13 NO2, m / z [M+H] + The theoretical value is 192.1019 and the actual value is 192.0986.

[0312] Example 13: Preparation of N,N-dimethyl-2-oxo-2-(m-tolyl)acetamide

[0313] (1) Preparation of m-Tolyl(triethylsilyl)ketone

[0314]

[0315] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of m-tolualdehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain m-tolyl-1,3-dithiane.

[0316] 2) Under nitrogen atmosphere at 0°C, n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to a solution of m-tolyl-1,3-dithiane (10.2mmol) in THF (10.0mL). After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain triethyl(2-(m-tolyl)-1,3-dithiane-2-yl)silane.

[0317] 3) Under 0°C air atmosphere, acetone and water (volume ratio of acetone: water is 6:7) were added to triethyl (2- (m-tolyl) -1,3-dithiane-2-yl) silane (2.857mmol), NBS (11.24mmol) was added thereto, and the reaction was continued for 30min. The mixture was diluted with water (10mL) and extracted with EtOAc (10mL), and anhydrous sodium sulfate was added to remove water and concentrated under reduced pressure (evaporation at 35°C for 40min). The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1), to obtain m-tolyl (triethylsilyl) ketone.

[0318] (2) Preparation of N,N-dimethyl-2-oxo-2-(m-tolyl)acetamide

[0319]

[0320] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of m-tolyl(triethylsilyl)ketone (0.3 mmol). After stirring for 1 hour, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=5:1) as the eluent to obtain N,N-dimethyl-2-oxo-2-(m-tolyl)acetamide (27.89 mg, 73%, compound 3m).

[0321] The structural characterization data of compound 3m are as follows:

[0322] from Fig.25 You can get: 1 H NMR (600MHz, CDCl3) δ7.72-7.73(m,2H),7.43-7.44(m,1H),7.36-7.39(m,1H),3.10(s,3H),2.94(s,3H),2.40(s,3H).

[0323] from Fig.26 You can get: 13 C NMR (150MHz, CDCl3) δ192.1,167.3,139.0,135.7,133.2,130.1,129.0,127.0,37.1,34.1,21.3.

[0324] HRMS(ESI): Molecular formula C 11 H 13 NO2, m / z [M+H] + The theoretical value is 192.1019 and the actual value is 192.1013.

[0325] Example 14: Preparation of 2-(3,5-dimethylphenyl)-N,N-dimethyl-2-oxoacetamide

[0326] (1) Preparation of (3,5-dimethylphenyl)(triethylsilyl)methanone

[0327]

[0328] 1) Under nitrogen atmosphere at 0°C, 1,3-propanedithiol (11.0 mmol) was added to a solution of 3,5-dimethylbenzaldehyde (10.0 mmol) in dichloromethane (10 mL), and then boron trifluoride ether (3 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then separated and purified by column chromatography, using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain 2-(3,5-dimethylphenyl)-1,3-dithiane.

[0329] 2) n-BuLi (2.5M, 6.08mL, 15.2mmol) and TESCl (10.2mmol) were added to a solution of 2-(3,5-dimethylphenyl)-1,3-dithiane (10.2mmol) in THF (10.0mL) at 0°C under nitrogen atmosphere. After stirring at 0°C for 30min, the reaction mixture was warmed to room temperature and stirred for 30min. Water (2mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure (evaporated at 35°C for 40min) and then separated and purified by column chromatography using petroleum ether / ethyl acetate (v / v=100:1) as the eluent to obtain (2-(3,5-dimethylphenyl)-1,3-dithiane-2-yl)triethylsilane.

[0330] 3) Under 0°C air atmosphere, acetone and water (acetone: water volume ratio is 6:7) were added to (2-(3,5-dimethylphenyl)-1,3-dithian-2-yl)triethylsilane (2.857mmol), and NBS (11.24mmol) was added thereto, and the reaction was carried out for 30min. The mixture was diluted with water (10mL) and extracted with EtOAc (10mL), and anhydrous sodium sulfate was added to remove the water and then concentrated under reduced pressure (evaporation at 35°C for 40min). The mixture was separated and purified by column chromatography, and the eluent used was petroleum ether / ethyl acetate (v / v=100:1), to obtain (3,5-dimethylphenyl)(triethylsilyl)methanone.

[0331] (2) Preparation of 2-(3,5-dimethylphenyl)-N,N-dimethyl-2-oxoacetamide

[0332]

[0333] Under a nitrogen atmosphere at -78°C, DMF (0.2 mmol) and LDA (2 mol / L, 0.35 mL, 0.7 mmol) were added to a THF solution (0.6 mL) of (3,5-dimethylphenyl)(triethylsilyl)methanone (0.3 mmol). After stirring for 1.5 hours, water (2 mL) was added to quench the reaction. The reaction was concentrated under reduced pressure (evaporated at 35°C for 40 min) and then separated and purified by column chromatography. The eluent used was petroleum ether / ethyl acetate (v / v=5:1) to give 2-(3,5-dimethylphenyl)-N,N-dimethyl-2-oxoacetamide (34.85 mg, 85%, compound 3n).

[0334] The structural characterization data of compound 3n are as follows:

[0335] from Fig. 27 You can get: 1 H NMR (600MHz, CDCl3) δ7.46(s,2H),7.19(s,1H),3.04(s,3H),2.87(s,3H),2.29(s,6H).

[0336] from Fig.28 You can get: 13 C NMR (150MHz, CDCl3) δ192.4,167.4,138.9,136.6,133.2,127.4,37.1,34.0,21.2.

[0337] HRMS(ESI): Molecular formula C 12 H 15 NO2, m / z [M+H] + The theoretical value is 206.1176 and the actual value is 206.1173.

[0338] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

Claims

1. A method for preparing a phenyl ketone amide compound, characterized in that: It includes the following steps: A phenyl acyl silicon compound 1 and an amide compound 2 are used as raw materials, a catalyst is added, and the reaction is carried out in a first solvent to prepare a phenyl ketone amide compound 3. The reaction route is any one of the following two reaction routes: The first reaction route: The second reaction route: Among them, the R1 group The ortho, meta and / or para position of the group; n is 1 to 3; The R1 group is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen or substituted C 1-6 wherein the substituent is selected from one or more of methyl, tert-butyl, methoxy, butoxy, -F and -Cl; The R2 group and the R3 group are independently selected from H or C 1-6 alkyl; The R4 group is a silicon-containing group; The R5 group is selected from Wherein, the R6 group is selected from H, C 1-7 Alkyl or C 1-7 of alkoxy.

2. The method for preparing the phenyl ketone amide compound according to claim 1, wherein: The silicon-containing group is a group in which the three substituents on the silicon atom are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, benzyl, C 1-3 Alkyl-substituted phenyl, styryl, hydroxy-substituted styryl or trimethylsilyl; Preferably, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, methylbutylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-dimethylphenylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, 2-hydroxystyryldiisopropylsilyl, tert-butyloxymethylphenylsilyl or tert-butoxydiphenylsilyl; More preferably, the silicon-based protecting group is trimethylsilyl or triethylsilyl.

3. The method for preparing the phenyl ketone amide compound according to claim 1 or 2, wherein: In the first or second reaction route, the R1 group is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, methoxy, butoxy or -Cl; And / or, in the first reaction route, R2 and R3 groups are independently selected from methyl, ethyl, propyl or n-butyl; or, in the second reaction route, R5 group is selected from 4. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 3, wherein: The molar ratio of the phenyl acyl silicon compound 1 to the amide compound 2 is 1-4:1-3; Preferably, the molar ratio of the phenyl acyl silicon compound 1 to the amide compound 2 is 2.5-3.5:1.5-2.5; More preferably, the molar ratio of the phenyl acyl silicon compound 1 to the amide compound 2 is 2.7-3.3:1.7-2.

3.

5. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 4, wherein: The reaction temperature is -110°C to -40°C; preferably, the reaction temperature is -100°C to -70°C; And / or, the reaction time is 0.5 to 5 hours.

6. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 5, wherein: The catalyst is selected from one or more of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; Preferably, the catalyst is selected from lithium diisopropylamide; More preferably, the molar ratio of the catalyst to the compound 1 is 1-8:1-4; More preferably, the molar ratio of the catalyst to the compound 1 is 6-8:2-4; Most preferably, the molar ratio of the catalyst to the compound 1 is 6.5-7.5:2.5-3.

5.

7. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 6, wherein: The first solvent includes one or more of tetrahydrofuran, methyl tert-butyl ether, toluene, ethyl ether and dichloromethane; Preferably, the first solvent is tetrahydrofuran; More preferably, the volume ratio of the amount of the compound 1 to the first solvent is 1:0.5-6, wherein the unit of the amount of the substance is mol and the unit of volume is L; Further preferably, the volume ratio of the amount of the compound 1 to the first solvent is 1:1-5, wherein the unit of the amount of the compound 1 is mol and the unit of the volume is L; More preferably, the volume ratio of the amount of the compound 1 to the first solvent is 1:1-3, wherein the unit of the amount of the compound 1 is mol and the unit of the volume is L.

8. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 7, wherein: After the reaction is completed, a second solvent is added to quench the reaction to obtain a phenylketoamide compound 3; Preferably, the second solvent is water or a saturated aqueous solution of ammonium chloride; More preferably, the ratio of the volume of the second solvent to the amount of the substance of compound 1 is 1 to 15:1, wherein the unit of the amount of the substance is mol and the unit of the volume is L; further preferably, the ratio of the volume of the second solvent to the amount of the substance of compound 1 is 5 to 8:1; And / or, preferably, adding a second solvent to quench the reaction, and then concentrating under reduced pressure; more preferably, the temperature of concentrating under reduced pressure is 20 to 50° C.; and / or, the time is 10 to 60 min; And / or, preferably, the product after reduced pressure concentration is purified, and the purification is column chromatography separation and purification; more preferably, the eluent is petroleum ether and ethyl acetate; further preferably, the volume ratio of petroleum ether to ethyl acetate is 2 to 15:

1.

9. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 8, wherein: The gas atmosphere during the preparation process is N2 gas atmosphere or Ar gas atmosphere.

10. The method for preparing the phenyl ketone amide compound according to any one of claims 1 to 9, wherein: The phenyl ketone amide compound 3 is any one of the following compounds: Compound 3a: n = 1, R1 is in the para position, R1 is -CH3, R2 is -CH3, and R3 is -CH3; Compound 3b: n=1, R1 is in the para position, R1 is -CH3, R2 is -CH2CH3, and R3 is -CH2CH3; Compound 3c: n = 1, R1 is in the para position, R1 is -CH3, R5 is Compound 3d: n=1, R1 is in the para position, R1 is -CH3, R2 is -CH2CH2CH3, and R3 is -CH2CH2CH3; Compound 3e: n=1, R1 is in the para position, R1 is -CH3, R2 is -CH2CH2CH2CH3, and R3 is -CH2CH2CH2CH3; Compound 3f: n = 1, R1 is in the para position, R1 is -CH3, R5 is Compound 3g: n = 1, R1 is in the para position, R1 is -H, R2 is -CH3, and R3 is -CH3; Compound 3h: n = 1, R1 is in the para position, R1 is -C(CH3)3, R2 is -CH3, and R3 is -CH3; Compound 3i: n = 1, R1 is in the para position, R1 is -Cl, R2 is -CH3, and R3 is -CH3; Compound 3j: n = 1, R1 is in the para position, R1 is -OCH3, R2 is -CH3, and R3 is -CH3; Compound 3k: n = 1, R1 is in the para position, R1 is -OCH2CH2CH2CH3, R2 is -CH3, and R3 is -CH3; Compound 3l: n = 1, R1 is in the ortho position, R1 is -CH3, R2 is -CH3, and R3 is -CH3; Compound 3m: n = 1, R1 is at the meta position, R1 is -CH3, R2 is -CH3, and R3 is -CH3; Compound 3n: n=2, R1 is in the meta position, R1 is -CH3, R2 is -CH3, and R3 is -CH3.

Images